Long duration anaesthesia in pigs with an infusion of alfaxalone and dexmedetomidine

Abstract Pigs are commonly maintained on total intravenous anaesthesia when used in comparative medical research to study controlled manual ventilation of the lung. In this case study, four pigs were anaesthetised with a total intravenous anaesthetic infusion of alfaxalone and dexmedetomidine for up to 24 h whilst being mechanically ventilated. Cardiovascular parameters, blood gas values and body temperature were minimally affected throughout the anaesthetic period. Additional analgesia is recommended when utilising this drug combination for procedures that involve noxious stimuli.


INTRODUCTION
In respiratory research, the similarities between the pig and the human lung have made the pig a common model in comparative medical research studying ventilation and respiration (Judge et al., 2014). To facilitate research into critical care ventilators using pigs, intravenous infusions of anaesthetic drugs may be used to maintain pigs at an anaesthetic plane such that they can be intubated to allow mechanical ventilation. Alfaxalone is a neuroactive steroid that is commercially available in an unpreserved (Alfaxan®) and preserved (Alfaxan® Multidose) formulation that is registered for use in veterinary medicine as an intravenous induction and maintenance anaesthetic agent in dogs and cats. In pigs, alfaxalone has been used to induce and maintain anaesthesia and reported to have minimal cardiovascular effects at clinical does rates (Bigby et al., 2017;Lervik et al., 2020;Santos Gonzalez et al., 2013). As such, alfaxalone is an alternative choice as an intravenous maintenance anaesthetic agent in the pig, particularly if there is a potential shortage of commonly used human drugs (e.g., propofol) such as during the COVID-19 pandemic. To the authors' knowledge, the use of an intravenous infusion of alfaxalone and dexmedetomidine to maintain long duration anaesthesia (12-24 h) has not previously been reported in pigs.
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All procedures were performed with approval from the University of

DISCUSSION
The median alfaxalone infusion rate in our study was comparable to other studies in pigs in which alfaxalone was infused alone (4.8 mg/kg/h) (Bigby et al., 2017). Similar alfaxalone infusion rates (5 mg/kg/h) in combination with ketamine 5 mg/kg/h and dexmedetomidine 4 μg/kg/h were reported in another study following premedication with ketamine and midazolam (Lervik et al., 2020). Both studies maintained anaesthesia for only 60 min, and it is likely that the preanaesthetic drugs influenced drug infusion rates during the short anaesthetic period. For example, Bigby et al. (2017) observed that in some animals (3/9), endotracheal intubation was possible with the premedication only and no additional induction drug was required.
The protocol used in the present study was suitable for immobilising the pigs for mechanical ventilation but would not be suitable for noxious interventions. This is evidenced by most animals requiring additional alfaxalone or methadone when stimulated to position for radiographs. Interestingly, similar findings were reported during the previously described short duration alfaxalone and alfaxaloneketamine-dexmedetomidine infusions with approximately 14%-35% of animals responding to epidural placement or dewclaw clamping, respectively (Bigby et al., 2017;Lervik et al., 2020). Alfaxalone is not an analgesic, and while information on dexmedetomidine in pigs is limited, it has been reported to provide significant analgesia when infused at 4 mcg/kg/h in combination with ketamine and propofol (Lervik et al., 2020). It is possible that increasing the dexmedetomidine infusion rate and perhaps the addition of an opioid to the infusion regime may have provided more consistent anti-nociception and a more balanced anaesthetic and analgesic technique.
Cardiovascular parameters monitored were within acceptable ranges for anaesthetised pigs, and mean arterial blood pressure did not fall below 60 mmHg in any animal despite periods of significant positive end expiratory pressure of up to 15 cmH 2 O and peak inspiratory pressures (PIP) often in excess of 25 cm H 2 O (see Table 2 for details).
This is in agreement with other studies investigating the cardiovascular Abbreviations: DAP, diastolic arterial pressure; ETCO 2 , end tidal carbon dioxide; FiO 2 , fraction of inspired oxygen; HR, heart rate; Hour, time from first blood gas sampling; I,E ratio, inspiratory to expiratory time ratio; MAP, mean arterial pressure; PEEP, peak end expiratory pressure; PIP, peak inspiratory pressures; PO 2 , partial pressure of oxygen in arterial blood; PCO 2 , partial pressure of carbon dioxide in arterial blood; RR, respiratory rate; SAP, systolic arterial pressure; SPO 2 , TV, tidal volume; oxygen saturation via pulse oximetry; Temp, temperature.
Previously, reports of alfaxalone (without preservative) infused alone or as part of a balanced anaesthetic technique in pigs have reported maintenance of anaesthesia for up to 60 minutes duration (Bigby et al., 2017;Duval et al., 2018;Lervik et al., 2020). To the authors knowledge, this is the first report of the preserved formulation of alfaxalone infused for 12-24 h to maintain anaesthesia in pigs. The formulation of alfaxalone used in the present study contains preservatives (ethanol, chlorocresol and benzethonium chloride); we are unable to rule out any possible toxicity or unforeseen effects these preservatives might have caused.
In conclusion, this study demonstrated that a combination of alfaxalone and dexmedetomidine is suitable to maintain long duration TIVA in pigs anaesthetised for controlled mechanical ventilation.